Low-affinity solfonylurea binding sites reside on neuronal cell bodies in the brain

Ambrose A. Dunn-Meynell, Vanessa H. Routh, Joseph J. McArdle, Barry E. Levin

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The antidiabetic sulfonylurea drugs bind to sites associated with an ATP-sensitive potassium (K(atp)) channel on cell bodies and terminals of neurons which increase their firing rates or transmitter release when glucose concentrations rise or sulfonylureas are present. High-affinity sulfonylurea binding sites are concentrated in areas such as the substantia nigra (SN) where glucose and sulfonylureas increase transmitter release from GABA neurons. But there is a paucity of high-affinity sites in areas such as the hypothalamic ventromedial nucleus (VMN) where many neurons increase their activity when glucose rises. Here we assessed both high- and low-affinity sulfonylurea binding autoradiographically with 20 nM [3H]glyburide in the presence or absence of Gpp(NH)p. Neurotoxin lesions with 6-hydroxydopamine (6-OHDA), 5,7-dihydroxytryptamine (5,7-DHT) and ibotenic acid were used to elucidate the cellular location of the two sites in the VMN, SN and locus coeruleus (LC). In the VMN, 25% of the sites were of low affinity. Neither 6-OHDA nor 5,7-DHT affected [3H]glyburide binding, while ibotenic acid reduced the number of VMN neurons and abolished low-affinity without changing high-affinity binding. In cell-attached patches of isolated VMN neurons, both 10 μM glucose and 100 μM glyburide decreased the open probability of the K(atp) channel suggesting that the low-affinity binding site resides on these neurons. In the SN pars reticulata, ibotenic acid reduced the number of neurons and high-affinity [3H]glyburide binding was decreased by 20%, while 6-OHDA had no effect. In the SN pars compacta, both 6-OHDA and ibotenic acid destroyed endogenous dopamine neurons and selectively ablated low-affinity binding. In the LC, 6-OHDA destroyed norepinephrine neurons and abolished low-affinity binding. These data suggest that low-affinity sulfonylurea binding sites reside on cell bodies of VMN, SN dopamine and LC norepinephrine neuron cell bodies and that high-affinity sites may be on axon terminals of GABA neurons in the SN.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalBrain research
Volume745
Issue number1-2
DOIs
StatePublished - Jan 16 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Keywords

  • Adenosine triphosphate (ATP)-sensitive potassium channel
  • Dopamine
  • Glibenclamide
  • Glucose
  • Hypothalamus
  • Locus coeruleus
  • Neurotoxin
  • Norepinephrine
  • Serotonin
  • Substantia nigra
  • γ-Aminobutyric acid (GABA)

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